1. Field of the Invention
The invention generally relates to compounds and methods that inhibit or disrupt microbial biofilms involved in infections in man and animals and in biofouling of surfaces susceptible to microbial accumulation.
2. Description of the Related Art
Bacteria often attach and accumulate on surfaces, enabling them to resist removal and killing by mechanical and chemical means. This can result in persistent and chronic infections and fouling of devices that are in contact with liquids containing the colonizing bacteria. Bacteria respond to signals resulting from the proximity, density, and identity of microbial neighbors. Through the process of quorum sensing (QS), bacteria can indirectly determine population density by sensing concentration of a secreted signal molecule (Bassler, 2002). The ability of bacteria to communicate with one another by QS and behave collectively as a group confers significant advantages, including more efficient proliferation, better access to resources and niches, and a stronger defense against competitors (Jefferson, 2004). Many QS systems having various effects on bacterial cell physiology have been studied. Examples include biofilm differentiation in Pseudomonas aeruginosa (Davies et al., 1998), swarming motility in Serratia liquefaciens (Eberl et al., 1999), competence development in Streptococcus pneumoniae (Lee and Morrison, 1999) and Streptococcus mutans (Li et al., 2001), and induction of virulence factors in Staphylococcus aureus (Ji et al., 1995).
Controlling bacterial biofilms is desirable for almost every human enterprise in which solid surfaces are introduced into non-sterile aqueous environments. U.S. Pat. No. 6,024,958 describes peptides that attempt to control biofilm formation by preventing bacterial adherence to teeth. In addition to occurrence in dental caries, medical examples of biofilm growth include cases involving indwelling medical devices, joint implants, prostatitis, endocarditis, and respiratory infections. In fact, the Centers for Disease Control and Prevention (CDC; Atlanta, Ga.) estimate that 65% of human bacterial infections involve biofilms. Non-medical examples of biofilm colonization are water and beverage lines, cooling towers, radiators, aquaculture contamination, submerged pumps and impellers, hulls of commercial, fishing and military vessels and literally every situation where biofouling occurs. The potential benefits of basic research focused at biofilm physiology and genetics with the ultimate goal of controlling surface-mediated microbial growth are limitless.
Interest in the study of biofilm-grown cells has increased partly because biofilm growth provides a microenvironment for cells to exist in a physical and physiological state that can increase their resistance to antimicrobial compounds and mechanical forces (reviewed in Costerton and Lewandowski, Adv Dent Res, 11:192-195). Growth in biofilms can also facilitate the transfer of genetic information between different species (Christensen et al. Appl Environ Microbiol, 64:2247-2255). Recent evidence suggests that biofilm-grown cells may display a dramatically different phenotype when compared with their siblings grown in liquid culture. In some, this altered physiological state has been shown to result from gene activation initiated by contact with surfaces (Finlay and Falkow. Microbiol. Molec Rev, 61:136-169) or from signal molecules produced by the bacteria allowing them to sense the cell density (quorum sensing) (Davies et al. Appl Environ Microbiol, 61:860-867). Biofilms may also act as ‘genotypic reservoirs’, allowing persistence, transfer and selection of genetic elements conferring resistance to antimicrobial compounds.
Streptococcus mutans is the principal etiological agent of dental caries in humans. None of the known types of S. mutans antibiotics has satisfactorily controlled caries. There is a need to identify new ways to control S. mutans induced caries.